The U.S. Government may have rights in this invention pursuant to National Institutes of Health Grant No. GM-15904 to Harvard Anesthesia Research and Teaching Center to C. Berde, and Grant No. CA 5257 to R. Langer.
This invention is generally in the field of anesthesiology and, in particular, the restoration and/or boosting of a previously administered local anesthesia by the use of a non-local anesthetic agent to reactivate and/or prolong local anesthesia.
Methods and/or formulations heretofore used to provided localized anesthesia are advantageously reversible so that nerve conduction and motor and/or sensory function returns. However, in many situations it becomes necessary to repeat the same local anesthesia one or more additional times in order to protect a patient from chronic pain or from pain induced by repeated surgical or medical procedures.
In order to provide local and/or anesthesia for extended periods, clinicians currently use local anesthetic agents administered through a catheter or syringe to a site where anesthesia is to be induced. Thus, prolonged local anesthesia, over a period of greater than about 6 hours, has heretofore required that local anesthetic be administered either as a bolus or through an indwelling catheter connected to an infusion pump. Similarly, heretofore, reactivation of local anesthesia has required repeated administered of a local anesthetic through an indwelling catheter or by re-injection. These methods have the disadvantage of potentially causing irreversible damage to nerves or surrounding tissues due to fluctuations in local anesthetic concentration and in the accumulation and diffusion of potentially toxic levels of local anesthetic into the systemic circulation.
One approach to this problem is to provide for a prolonged, sustained local anesthesia, as is disclosed by WO 94/05265. This published international patent application describes improved biocompatible controlled release systems consisting of a polymeric matrix incorporation of a local anesthetic for the prolonged administration of the local anesthetic agent. The devices are selected on the basis of their degradation profiles: release of the local anesthetic in a linear, controlled manner over the period of preferably two weeks and degradation in vivo with a half-life ranging from less than six months to about a year and more, and preferably from about two to four weeks, to induce localized anesthesia. The anti-inflammatories that are said to be useful include steroids such as dexamethasone, cortisone, prednisone, and others routinely administered orally or by injection. The exemplified pellet formulations comprise only about 20% local anesthetic and this published international patent application teaches that the selection of the polymers is critical to providing a sustained release of the local anesthetic agent. This publication also teaches that the anti-inflammatory agent serves to prevent localized tissue inflammation and encapsulation of the injection site with a connective tissue capsule. However, the local anesthesia so provided is of necessity prolonged, without any option for modulating the level of anesthesia.
Local anesthetic agents have been incorporated into biocompatible polymeric devices, such as, for example, polylactic acid microspheres, as described by Wakiyama, et al., Chem. Pharm. Bull., 30:3719-3727 (1982). In contrast to the lipid based materials, the poly(lactic acid) devices take over a year to degrade and cause localized inflammation. Berde, et al., Abstracts of Scientific Papers, 1990 Annual Meeting, Amer. Soc. Anesthesiologists, 73: A776 (September 1990), reported the use of a device formed of a polyanhydride polymer matrix of copolymer 1,3 bis (p-carboxyphenoxy)propane and sebacic acid, in a ratio of 1:4, into which dibucaine free base was incorporated by compression molding. This drug-polymer device, however, had several drawbacks. For example, because the drug was incorporated into the polymer matrix by compression molding, the device sometimes displayed bulk erosion, causing fast initial release of drug.
Nevertheless, heretofore there has been no method or formulations known to the art for reactivating, prolonging or otherwise boosting a previously administered local anesthesia without the use of repeated dose of a local anesthetic.
Accordingly, it is an object of the present invention to provide methods and compositions for modulating local anesthesia by administering one or more glucocorticosteroid agents (also referred to herein as glucocorticoid agents) before, simultaneously with or after the administration of a local anesthetic at a site in a patient. It is a further object of the present invention to provide methods and compositions that are able to reactivate or prolong local anesthetic activity that has previously diminished or worn off.
It is a still further object of the present invention to provide methods and compositions for modulating the degree of local anesthesia wherein the active restorative or prolonging agents are pharmaceutically acceptable glucocorticosteroids that are locally or systemically administered to a patient needing or desiring to restore a previously induced local anesthesia.